Moro O. Salifu

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND Early identification of anemia of chronic kidney disease may be important for the development of preventive strategies. We compared anemia prevalence and characteristics in the National Kidney Foundation Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004 populations. METHODS Clinical, demographic, and laboratory data were collected from August 2000 to December 31, 2006, from participants in KEEP, a community-based health-screening program targeting individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. Anemia was defined as hemoglobin level less than 13.5 g/dL for men and less than 12.0 g/dL for women (Kidney Disease Outcomes Quality Initiative [KDOQI] 2006) or less than 13.0 g/dL for men and less than 12.0 g/dL for women (World Health Organization [WHO]). RESULTS In KEEP (n = 70,069), 68.3% of participants, and in NHANES (n = 17,061), 52% of participants, were women. African Americans represented 33.9% of the KEEP and 11.2% of the NHANES cohorts, and Hispanics comprised 12.4% of KEEP and 13.2% of NHANES. Using the KDOQI classification, anemia was present in 13.9% and 6.3% of KEEP and NHANES participants, whereas using the WHO classification, anemia was present in 11.8% and 5.3%, respectively. In adjusted analysis of KEEP data, KDOQI-defined anemia was significantly more likely in men (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.23 to 1.37); this pattern was reversed when using WHO-defined anemia (OR, 0.68; 95% CI, 0.64 to 0.72). Adjusted odds of anemia were greater for African American than white KEEP participants (OR, 2.98; 95% CI, 2.80 to 3.16; OR, 3.00; 95% CI, 2.81 to 3.20 for KDOQI- and WHO-defined anemia, respectively). CONCLUSION Anemia was twice as common in the targeted KEEP chronic kidney disease screening program cohort than in the NHANES sample population. African Americans had a 3-fold increased likelihood of anemia compared with whites. Targeted screening can identify anemia in a high-risk population.

Commercialization of kidney transplants: a systematic review of outcomes in recipients and donors

In this study we systematically reviewed outcomes in recipients and donors of commercial kidney transplants. Inherent in a study of this nature is the possibility of center and country bias, in particular there are no publications from China and South America. Publications also tended to report poor outcomes which may reflect bias on the part of the authors or to highlight the ethical issues in this area. We were unable to perform a meta-analysis due to variability in studies making it impossible to synthesize the data other than descriptive. Furthermore, these studies were not large or well conducted. We found that patient and graft survival was generally inferior to the data obtained from the UNOS (United Network for Organ Sharing). Some studies did achieve good outcomes, however, due to lack of details, it was not possible to infer if the donor hospital, surgical technique or immunosuppressive regimen was a factor. There was a higher incidence of unconventional and life-threatening infections such as malaria, invasive fungal infections, pneumonia, HIV and hepatitis. There was also a markedly increased incidence of postoperative surgical interventions in recipients. We suggest the establishment of a database for both recipients and donors to identify unique surgical, medical, infectious and immunosuppressive protocols for the recipients and donors in these hospitals. This could lead to better liaison between the recipient and donor hospitals so that modern surgical and medical practices can be implemented. There should also be improved emotional and psychological support to both the recipient and the donor. However, these steps could be seen as condoning the reprehensible practice of commercialization of human body parts.

The F11 receptor (F11R/JAM-A) in atherothrombosis: Overexpression of F11R in atherosclerotic plaques

F11R is the gene name for an adhesion protein, called the F11-receptor, aka JAM-A, which under normal physiological conditions is expressed constitutively on the surface of platelets and localized within tight junctions of endothelial cells (EC). Previous studies of the interactions between human platelets and EC suggested that F11R/JAM-A plays a crucial role in inflammatory thrombosis and atherosclerosis. The study reported here obtained in-vivo confirmation of this conclusion by investigating F11R/JAM-A protein and mRNA in patients with aortic and peripheral vascular disease and in an animal model of atherosclerosis. Molecular and immunofluorescence determinations revealed very high levels of F11R/JAM-A mRNA and F11R/JAM-A protein in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with 12-week-old atherosclerosis-prone apoE-/- mice, an age in which atherosclerotic plaques are well established. Enhanced expression of the F11R/JAM-A message in cultured EC from human aortic and venous vessels was observed following exposure of the cells to cytokines. Determinations of platelet adhesion to cultured EC inflamed by combined cytokine treatment in the presence of F11R/JAM-A - antagonists provided data indicating that de novo expression of F11R/JAM-A on the luminal surface of inflamed EC has an important role in the conversion of EC to a thrombogenic surface. Further studies of these interactions under flow conditions and under in-vivo settings could provide a final proof of a causal role for F11R/JAM-A in the initiation of thrombosis. Based on our in-vitro and in-vivo studies to date, we propose that therapeutic drugs which antagonize the function of F11R/JAM-A should be tested as novel means for the prevention and treatment of atherosclerosis, heart attacks and stroke.

Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study Equations: Prevalence of and Risk Factors for Diabetes Mellitus in CKD in the Kidney Early Evaluation Program (KEEP)

BACKGROUND Diabetes is a leading cause of chronic kidney disease (CKD). Whether reclassification of CKD stages based on glomerular filtration rate estimated using the CKD Epidemiology Collaboration (CKD-EPI) equation versus the Modification of Diet in Renal Disease (MDRD) Study equation modifies estimates of prevalent risk factors across stages is unknown. METHODS This is a cross-sectional analysis of data from the Kidney Early Evaluation Program (KEEP), a community-based health screening program targeting individuals 18 years and older with diabetes, hypertension, or a family history of diabetes, hypertension, or kidney disease. Of 109,055 participants, 68.2% were women and 31.8% were African American. Mean age was 55.3 ± 0.05 years. Clinical, demographic, and laboratory data were collected from August 2000 through December 2009. Glomerular filtration rate was estimated using the CKD-EPI and MDRD Study equations. RESULTS CKD was present in 25.6% and 23.5% of the study population using the MDRD Study and CKD-EPI equations, respectively. Diabetes was present in 42.4% and 43.8% of participants with CKD, respectively. Prevalent risk factors for diabetes included obesity (body mass index >30 kg/m(2)), 44.0%; hypertension, 80.5%; cardiovascular disease, 23.2%; family history of diabetes, 55.9%; and dyslipidemia, 43.0%. In a logistic regression model after adjusting for age and other risk factors, odds for diabetes increased significantly compared with no CKD with each CKD stage based on the CKD-EPI equation and similarly with stages based on the MDRD Study equation. Using a CKD-EPI-adjusted model, ORs were: stage 1, 2.08 (95% CI, 1.90-2.27); stage 2, 1.86 (95% CI, 1.72-2.02); stage 3, 1.23 (95% CI, 1.17-1.30); stage 4, 1.69 (95% CI, 1.42-2.03); and stage 5, 2.46 (95% CI, 1.46-4.14). CONCLUSIONS Using the CKD-EPI equation led to a lower prevalence of CKD but to similar diabetes prevalence rates associated with CKD across all stages compared with the MDRD Study equation. Diabetes and other CKD risk factor prevalence was increased compared with the non-CKD population.

Hypertension After Renal Transplant

Hypertension is common after renal transplant and is associated with adverse graft and patient outcomes. A thorough understanding of the unique factors that operate in renal transplant recipients is essential for the proper evaluation and management of this disorder. In this review, the authors outline the pathogenesis, diagnostic workup, and treatment of hypertension after renal transplant.

Elevated Plasma Level of Soluble F11 Receptor/Junctional Adhesion Molecule-A (F11R/JAM-A) in Hypertension

BACKGROUND The F11 receptor (F11R, also known as junctional adhesion molecule A (JAM-A)) plays a role in the development of hypertension in rat. Genetic variants in the human F11R gene were demonstrated to influence systolic blood pressure. In the present study, we investigated the relationship between F11R and hypertension by examining the levels of a circulating soluble form of F11R (sF11R) in hypertensive patients. METHODS Plasma sF11R was measured by enzyme-linked immunosorbent assay in 152 hypertensive and 166 normotensive subjects in whom seven tagging single-nucleotide polymorphisms (SNPs) in the F11R gene had been genotyped. RESULTS Plasma sF11R levels were significantly higher in hypertensive subjects than in normotensive subjects (median (interquartile) range): 162.8 (85.5-293.2) vs. 116.5 (74.1-194.8) pg/ml, P = 0.004), which remained significantly higher after adjusting for age, sex, body mass index (BMI), and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028). In stepwise multiple logistic regression, sF11R level (log-transformed) (P = 0.040), triglycerides (log-transformed) (P = 0.024), and HOMA-IR (log-transformed) (P < 0.001) were independently associated with hypertension. Plasma sF11R level correlated with systolic and diastolic blood pressures (r = 0.15, P < 0.001, and r = 0.13, P = 0.024, respectively). In stepwise multiple linear regression, hypertension (P = 0.013) and fibrinogen levels (P = 0.027) were significant independent predictors of sF11R level. A seven-locus haplotype, present in 2.1% of the subjects, was associated with higher sF11R level (P = 0.024). CONCLUSIONS These results further support a role of F11 receptor in the pathophysiology of human hypertension.

Alcohol consumption and blood pressure in the adult US population: assessment of gender-related effects.

Objective Our objective was to assess the gender-related effects of alcohol consumption on blood pressure (BP) in a representative sample of the adult US population. Methods We examined data from the National Health and Nutrition Examination Survey 1999–2000. The effects of various risk factors for hypertension on BP were examined with analysis of covariance statistics. Results Of the 5448 adults over 20 years of age, 2650 (48.7%) reported the intake of one or more drinks per day over the past year. In this population, the mean ± SEM age was 46.9 ± 0.34 years, the body mass index was 24.8 kg/m2, 1257 (47.4%) were women, systolic BP was 124.3 ± 0.44 mmHg and diastolic BP was 72.7 ± 0.27 mmHg. Hypertension was reported in 21.1%, diabetes in 5.1% and cigarette smoking in 39.7%. A significant effect on systolic BP was shown with age (P < 0.01), body mass index (P < 0.01), race (P = 0.01), gender (P < 0.01) and diabetes (P < 0.01). The interaction with gender and alcohol drinking level was significant (P = 0.02). Post-hoc analysis localized the source of this effect. There was a significant increase in systolic BP between one and three and between one and four, but not between one and two, drinks per day in men. This effect was not observed in women. Conclusion Consistent with previous reports, our study suggests that alcohol intake up to two drinks per day has no effect on BP. There was a gender-related effect of alcohol intake in excess of two drinks per day on BP, with increased BP observed only in men but not in women.

COMMON ILIAC ARTERY STENOSIS PRESENTING AS RENAL ALLOGRAFT DYSFUNCTION IN TWO DIABETIC RECIPIENTS

Background. Suprarenal common iliac artery stenosis is an uncommon but reversible cause of allograft dysfunction in renal transplant recipients. Method. We describe two diabetic renal transplant recipients with worsening hypertension, edema, and azotemia. Magnetic resonance angiography (MRA) demonstrated tight stenoses in the common iliac artery proximal to the allograft anastomosis site with patent renal transplant artery in both cases. These findings were later confirmed with carbon dioxide angiography. Results. No acute rejection was noted on renal biopsy in either case. Placement of percutaneous iliac artery Wallstents resulted in decrease of serum creatinine from 6.5 to 2.0 mg/dl and 1.7 to 1.0 mg/dl within 2 and 4 weeks, respectively. Conclusion. Common iliac artery stenosis should be suspected in renal transplant recipients presenting with worsening hypertension, edema and azotemia. MRA for screening followed by carbon dioxide angiography and placement of intravascular stents for focal vascular obstructive lesions reverses allograft dysfunction.

Incidence, predictors, costs, and outcome of renal cell carcinoma after kidney transplantation: USRDS experience.

Introduction. We carried out an analysis of the United States Renal Data System to determine the incidence, risk factors, prognosis, and costs associated with the diagnosis of renal cell carcinoma (RCC) after kidney transplantation. Methods. This is a retrospective cohort of 40,821 Medicare primary renal transplant recipients transplanted from January 1, 2000, to July 1, 2005, and followed up till December 31, 2005, excluding those with prior RCC or nephrectomy. Kaplan-Meier analysis was performed to determine the time of occurrence of RCC, and Cox regression was used to determine factors associated with RCC. Results. Three hundred sixty-eight patients were diagnosed with RCC within 3 years after transplant (incidence of 3.16 per 1000 person years). The 3-year incidence of RCC posttransplant was 9.29 per 1000 person years (2.3%) for those with pretransplant cysts and 3.08 per 1000 person years (0.7%) without pretransplant cysts. RCC was diagnosed disproportionately early posttransplant in patients with cysts. Cysts were independently associated with increased risk of RCC, as was male gender, older recipient, donor age, African American recipient, increased time on dialysis and acute rejection within first year posttransplant. RCC was associated with increased risk of mortality with a higher risk with pretransplant cysts. Patients who developed RCC had higher cumulative median costs (